Cholinergic agonists as novel treatments for schizophrenia: the promise of rational drug development for psychiatry.
Cholinergic agonists as novel treatments for schizophrenia: the promise of rational drug development for psychiatry.
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胆碱能激动剂作为精神分裂症的新疗法：精神病学合理药物开发的前景。
DOI：
10.1176/appi.ajp.2008.08050769
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Moore,Holly
中科院分区：
文献类型：
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作者：
Lieberman,JeffreyA;Javitch,JonathanA;Moore,Holly
几十年来，精神病学和精神药理学领域一直在拼命寻找具有新作用机制的新药，以改善精神分裂症的治疗。回顾我们的精神分裂症药典，这似乎是一个令人生畏的，如果不是堂吉诃德式的追求，特别是如果我们增加了开发作用于多巴胺以外靶点的药物的挑战。这可能是由于这样一个事实，即历史上推动我们在治疗学领域向前发展的大多数发现都是偶然发现的，而不是来自合理的药物开发过程，其中药物是基于来自病因学或病理生理学理论的靶点开发的。在本期杂志上，弗里德曼等人的研究结果。(1)和Shekhar et al. (2)两种新的化合物通过不同的机制作为胆碱能激动剂起作用，这表明潮流可能正在转向，合理的药物开发可能已经进入精神病学。人们早就知道乙酰胆碱在认知中起着重要作用，胆碱能传递受损会导致阿尔茨海默病的认知缺陷（3）。有证据表明，精神分裂症患者的毒蕈碱受体和烟碱受体数量均减少（4，5），α7烟碱受体的功能多态性与该疾病存在遗传关联（6）。此外，乙酰胆碱调节纹状体（7，8）和皮质（10）中的多巴胺传递，纹状体中的多巴胺失调可能导致阳性和阴性症状（9），皮质中的多巴胺传递缺陷被认为会导致认知缺陷（9，10）。沿着这些发现，以及精神分裂症患者大量消耗尼古丁（11），以及氯氮平或其活性代谢物的毒蕈碱受体激动作用可能是其潜在改善阴性和认知症状的基础的建议，引起了对胆碱能激动剂治疗精神分裂症及其认知缺陷的兴趣（10，12）。1）烟碱乙酰胆碱受体，其是由不同α和β亚基的五聚体组合以及同聚体α7烟碱受体形成的配体门控离子通道，和2）毒蕈碱受体M1-M5（8，13）。烟碱受体的激活导致钠和/或钙电导的快速增加，从而增加神经元活性和神经递质释放（8）。另一方面，毒蕈碱受体信号传导由G蛋白介导，发挥较慢但可能更持久的作用（13）。乙酰胆碱广泛分布在大脑中，然而，它在新皮层、海马和纹状体以及中脑多巴胺神经元中的作用可能与精神分裂症的胆碱能治疗最相关。新皮层和海马分别从主要位于Meynert基底核和内侧隔的基底前脑神经元接收胆碱能输入（3）（图1A）。纹状体接受大量皮质输入，高度集中于从局部胆碱能中间神经元释放的乙酰胆碱（8）（图1B）。新大脑皮层，臀部-
For several decades the fields of psychiatry and psychopharmacology have been engaged in a desperate search for new drugs with novel mechanisms of action to improve the treatment of schizophrenia. From reviewing our pharmacopeia for schizophrenia it appears that this has been a daunting, if not quixotic, quest, particularly if we add the challenge of developing drugs that act on targets other than dopamine. This could likely be due to the fact that most of the discoveries that have historically propelled our field forward in therapeutics have come through serendipity and not from a process of rational drug development in which drugs are developed on the basis of targets derived from theories of etiology or pathophysiology. In this issue of the Journal, the results of studies by Freedman et al.(1) and Shekhar et al.(2) with two novel compounds acting through different mechanisms as cholinergic agonists suggest that the tide may be turning and that rational drug development may have arrived in psychiatry. It has long been known that acetylcholine plays an important role in cognition and that impaired cholinergic transmission contributes to the cognitive deficits in Alzheimer’s disease (3). There is evidence for decreased numbers of both muscarinic and nicotinic receptors in schizophrenia (4, 5), and a functional polymorphism of the α7 nicotinic receptor has been linked genetically to this disorder (6). Moreover, acetylcholine modulates dopamine transmission in the striatum (7, 8), where dopamine dysregulation may contribute to both positive and negative symptoms (9), and in the cortex (10), where dopamine transmission deficits have been postulated to contribute to cognitive deficits (9, 10). These findings, along with the heavy consumption of nicotine by patients with schizophrenia (11) and the suggestion that muscarinic receptor agonism by clozapine or its active metabolite may underlie its potential amelioration of negative and cognitive symptoms, have raised interest in cholinergic agonists to treat schizophrenia and its cognitive deficits (10, 12).Cholinergic transmission is mediated by two families of receptors: 1) nicotinic acetylcholine receptors, which are ligand-gated ion channels formed by pentameric combinations of different α and β subunits, as well as homomeric α7 nicotinic receptors, and 2) the muscarinic receptors M1–M5 (8, 13). Activation of nicotinic receptors leads to a rapid increase in sodium and/or calcium conductance that increases neuron activity and neurotransmitter release (8). Muscarinic receptor signaling, on the other hand, is mediated by G proteins exerting slower but potentially more sustained effects (13). Acetylcholine is widely distributed in the brain; however, its actions in the neocortex, hippocampus, and striatum, and at midbrain dopamine neurons, are of perhaps the greatest relevance to cholinergic therapies in schizophrenia. The neocortex and hippocampus receive cholinergic input from basal forebrain neurons located primarily in the nucleus basalis of Meynert and medial septum, respectively (3)(Figure 1A). The striatum, which receives massive cortical input, is highly concentrated in acetylcholine that is released from local cholinergic interneurons (8)(Figure 1B). The neocortex, hip-